Project Summary/Abstract Acoustic Droplet Ejection (ADE) enables non-contact dispensing and is considered state-of-the-art for high throughput, plate-based approaches that interrogate the effect of small molecules (e.g. drug-like chemicals, natural products, etc.), siRNA's, peptides, and other agents on biological systems and disease models. Non- contact dispensing of collections or ?libraries? of these perturbagens is essential to assessing their true impact in biological assays and plays a key role in informing downstream activities that are designed to develop useful probes of biological processes and/or potential drug candidates for novel therapeutic approaches. At UT Southwestern, the HTS Core is engaged in helping to identify and develop useful chemical probes for drug target discovery and in supporting hit-to-lead optimization in pre-clinical drug discovery programs. In this context, the Core functions collaboratively with principal investigators with expertise in biology, chemistry, biochemistry, pharmacology, biophysics, and bioinformatics to exploit novel discoveries in biology and the pathology of disease for the development of new therapeutic approaches for unmet medical need. Importantly, the Core uses an ADE instrument, an Echo555 (Labcyte, Inc.), to transfer small chemical molecules to experiments that are part of high throughput screens, HTS hit confirmation studies, dose-response studies, drug combinations studies, hit-to-lead optimization studies, and bioassay-guided fractionation of natural products. ADE instruments play a key role in drug discovery research programs by dispensing nanoliter volumes of test compounds and libraries with high accuracy and precision. It avoids the artifacts of contact dispensing (compound carry over and compound loss) that can lead to erroneous assessments of test compound activity, which ultimately misinforms downstream experiments. Our current ADE instrument, an Echo555, is nearing end-of-life and must be replaced in order for the HTS Core to productively and efficiently support NIH-sponsored research at UT Southwestern. For this proposal, we have selected a new Echo555 as our proposed ADE instrument. If our proposal is funded, we will, of course, re-evaluate all ADE instruments at that time and select the state-of-the-art instrument for our facility.